Diaromatic compounds derived from a salicylic unit and their use in human and veterinary medicine and in cosmetics

ABSTRACT

Diaromatic compounds, characterized in that they correspond to the following general formula: ##STR1## in which: R 1  is --CH 3 , --CH 2  OH, --COR 8  or --CH 2  OCOR 9 , R 8  is H, OH, --OR 10 , --N(rr&#39;) or alkyl, R 10  is alkyl, alkenyl, aryl or aralkyl, r and r&#39; being H, alkyl, aryl, aralkyl, etc., r and r&#39; together form a heterocycle, R 9  is alkyl, alkenyl or a sugar residue, R 2  and R 3  are --OR 11  or --OCOR 11 , R 11  is H, alkyl, fluoroalkyl, aryl or aralkyl, R 3  in addition being H, R 4  is H, OH, alkyl, alkoxy, F, Cl or --CF 3 , R 5  and R 7  are H, OH, alkoxy, α-substituted alkyl or α,α&#39;-disubstituted alkyl, etc., R 6  is H, OH, alkyl, alkoxy, cycloalkyl, etc., R 5  and R 7  cannot simultaneously be OH or alkoxy and R 4 , R 5 , R 6  and R 7  cannot simultaneously be H, R 5  and R 6  or R 6  and R.sub. 7 can form, with the aromatic ring, a ring with 5 or 6 members, X is chosen from amongst: 
     (i) --C(R 13  R 14 )--C(R 16  R 18 )--W--, (ii) --C(R 14  R 16 )--W--C(R 18  R 19 )--, (iii) --C(R 13  R 14 )--C(R 15  R 16 )--C(R 18  R 20 )--, 
     (iv) --CR 17  ═CR 21  --C(R 13  R 14 )--, 
     W is O, --NR 12  or S(O) n , n=0, 1 or 2, R 13 , R 15  and R 20  are H, --OR 11 , --OCOR 11  etc. , R 14 , R 16 , R 18  and R 19  are H, aralkyl, alkyl, etc., when X is (i) R 13  and R 14  can form ═N--OR 11  or ═N--OCOR 11 , when X is (iii) or (iv), R 14 , R 16  and R 18  are also --OR 11  or --OCOR 11 , or R 13 , R 14  or R 15 , R 16  taken together can form ═NOR 11  or ═N--OCOR 11 , R 12  is H, alkyl, aralkyl, alkenyl, alkynyl or fluoroalkyl, R 17  is H, hydroxyl, alkyl or alkoxy, R 21  is H or alkyl, and the salts of the compounds of formula (I).

FIELD OF THE INVENTION

This application is a 371 of PCT/FR92/00414, filed May 13, 1992.

The present invention relates to novel diaromatic compounds derived froma salicylic unit, a process for their preparation and their use in humanand veterinary medicine and in cosmetics.

These novel compounds are used in the topical and systemic treatment ofdermatological conditions connected with a disorder of keratinisation(differentiation/proliferation) and dermatological or other conditionswith an inflammatory and/or immunoallergic component and in degenerativediseases of the connective tissue, and have an antitumour activity. Inaddition, these compounds can be used in the treatment of atopy, be itcutaneous or respiratory, and of rheumatoid psoriasis. They are alsoused in the ophthalmological field, especially in the treatment ofcorneopathies.

SUMMARY OF THE INVENTION

The compounds according to the invention can be represented by thefollowing general formula: ##STR2## in which: R₁ represents the --CH₃radical, the --CH₂ OH radical, the --COR₈ radical or the --CH₂ OCOR₉radical,

R₈ representing a hydrogen atom, OH, --OR₁₀, ##STR3## or a lower alkylradical, R₁₀ representing an alkyl radical having 1 to 20 carbon atoms,an alkenyl radical having 2 to 20 carbon atoms, or an aryl or aralkylradical,

r and r' identical or different, representing a hydrogen atom, a loweralkyl radical, an aryl radical, an aralkyl radical, an α-aminoacidresidue, a sugar residue or a heterocycle or r and r' taken togetherforming a heterocycle,

R₉ representing an alkyl radical having 1 to 20 carbon atoms, an alkenylradical having 2 to 20 carbon atoms or a sugar residue,

R₂ and R₃ represent --OR₁₁ or --OCOR₁₁

R₁₁ representing a hydrogen atom, a lower alkyl radical, a fluoroalkylradical having 1 to 6 carbon atoms and 3 to 7 fluorine atoms, an arylradical or an aralkyl radical, it being possible for R₃ to additionallyrepresent a hydrogen atom,

R₄ represents a hydrogen atom, OH, a lower alkyl radical, an alkoxyradical having 1 to 6 carbon atoms, a fluorine or chlorine atom or the--CF₃ group,

R₅ and R₇ represent a hydrogen atom, OH, an alkoxy radical having 1 to 6carbon atoms, an α-substituted alkyl radical having 3 to 12 carbon atomsor an α,α'-disubstituted alkyl radical having 4 to 12 carbon atoms, acycloalkyl radical having 3 to 12 carbon atoms, a mono- or polycyclicradical having 5 to 12 carbon atoms connected to the phenyl ring by atertiary carbon, it not being possible for R₅ and R₇ to simultaneouslyrepresent OH or alkoxy,

R₆ represents a hydrogen atom, OH, a lower alkyl radical, an alkoxyradical having 1 to 6 carbon atoms, a cycloalkyl radical having 3 to 12carbon atoms, a monohydroxyalkyl radical, a polyhydroxyalkyl radical, afluorine atom, a chlorine atom, an alkenyl radical having 2 to 6 carbonatoms or an alkenyloxy radical having 2 to 6 carbon atoms, it not beingpossible for R₄, R₅, R₆ and R₇ to simultaneously represent a hydrogenatom,

R₅ and R₆ or R₆ and R₇ taken together can form, together with theadjacent aromatic ring, a ring with 5 or 6 members optionallysubstituted by methyl groups and/or optionally interrupted by an oxygenor sulphur atom,

X is a divalent radical which can be read from left to right orconversely, chosen amongst the group formed by:

(i) --C(R₁₃ R₁₄)--C(R₁₆ R₁₈)--W--

(ii) --C(R₁₄ R₁₆)--W--C(R₁₈ R₁₉)--

(iii) --C(R₁₃ R₁₄)--C(R₁₅ R₁₆)--C(R₁₈ R₂₀)--

(iv) --CR₁₇ ═CR₂₁ --C(R₁₃ R₁₄)--

in which:

W represents an oxygen atom, the --NR₁₂ group or the S(O)n group, nbeing 0, 1 or 2,

R₁₃, R₁₅ and R₂₀ represent a hydrogen atom, the --OR₁₁, --OCOR₁₁, or--NHCOR₁₁ radical, an ##STR4## radical, an aralkyl radical, a loweralkyl radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical,

r" and r"', identical or different, representing a hydrogen atom, alower alkyl radical, an alkenyl radical having 2 to 6 carbon atoms or analkynyl radical having 2 to 6 carbon atoms,

R₁₄, R₁₆, R₁₈ and R₁₉ represent a hydrogen atom, an aralkyl radical, alower alkyl radical, or a monohydroxyalkyl or polyhydroxyalkyl radical,

when X represents (i) , R₁₃ and R₁₄ can form a group ═N--OR₁₁ or a group═N--OCOR₁₁,

and when X represents (iii) or (iv), R₁₄, R₁₆ and R₁₈ can also representthe --OR₁₁ radical or the --OCOR₁₁ radical, oxo, or else R₁₃, R₁₄ orR₁₅, R₁₆ taken together can fore a group ═NOR₁₁ or a group ═N--OCOR₁₁,

R₁₂ representing a hydrogen atom, a lower alkyl radical, an aralkylradical, an alkenyl radical having 2 to 6 carbon atoms, an alkynylradical having 2 to 6 carbon atoms or a fluoroalkyl radical having 1 to6 carbon atoms and 3 to 7 fluorine atoms,

R₁₇ representing a hydrogen atom, a hydroxyl group, a lower alkylradical or an alkoxy radical having 1 to 6 carbon atoms,

R₂₁ representing a hydrogen atom or a lower alkyl radical,

and the salts of the compounds of formula (I) when R₁ represents acarboxylic acid function or when R₁₃, R₁₆ or R₂₀ represents an aminefunction, and the optical isomers of the compounds of formula (I).

DESCRIPTION OF PREFERRED EMBODIMENTS

When the compounds according to the invention are present in the form ofsalts, in the case where R₁ represents a carboxylic function these aresalts of an alkali or alkaline earth metal or else of zinc or of anorganic amine, in the case where R₁₃ or R₁₅ or R₂₀ represents an aminegroup these are pharmaceutically or cosmetically acceptable salts formedby addition of an inorganic or organic acid chosen from amongsthydrochloric, sulphuric, acetic, citric, fumaric, hemisuccinic, maleicand mandelic acid.

Lower alkyl radical is understood as meaning a radical having 1 to 6carbon atoms and preferably the methyl, ethyl, isopropyl, butyl andtertiary butyl radicals.

Alkoxy radical having 1 to 6 carbon atoms may especially be understoodas meaning a methoxy, ethoxy, isopropoxy or butoxy radical.

α-Substituted alkyl radical having 3 to 12 carbon atoms may especiallybe understood as meaning an isopropyl, 1-methylpropyl or 1-ethylpropylradical.

α,α'-Disubstituted alkyl radical having 4 to 12 carbon atoms mayespecially be understood as meaning a tert-butyl, 1,1-dimethylpropyl,1-methyl-1-ethylpropyl, 1-methyl-1-ethylhexyl or 1,1-dimethyldecylradical.

Monohydroxyalkyl radical may be understood as meaning a radical havingfrom 1 to 6 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropylor 3-hydroxypropyl radical.

Polyhydroxyalkyl radical may be understood as meaning a radicalcontaining from 2 to 6 carbon atoms and from 2 to 5 hydroxyl groups,such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.

Aryl radical may be understood as meaning a phenyl radical optionallysubstituted by at least one halogen atom, one hydroxyl or one nitrofunction.

Aralkyl radical may be understood as meaning the benzyl or phenethylradical optionally substituted by at least one halogen atom, onehydroxyl or one nitro function.

Cycloalkyl radical having 3 to 12 carbon atoms may be understood asmeaning especially a cyclopentyl or cyclohexyl radical.

Mono- or polycyclic cycloalkyl radical having 5 to 12 carbon atoms ofwhich the bonding carbon is trisubstituted can be understood as meaningthe 1-methylcyclohexyl or 1-adamantyl radical.

Alkenyloxy radical having 2 to 6 carbon atoms may be understood asmeaning linear or branched radicals, especially allyloxy and vinyloxy.

Alkenyl radical having 2 to 6 carbon atoms may be understood as meaningespecially the vinyl, allyl or 2-butenyl radicals.

Alkynyl radical having 2 to 6 carbon atoms may be understood as meaningespecially the propargyl radical.

Fluoroalkyl radical having from 1 to 6 carbon atoms and from 3 to 7fluorine atoms is understood as meaning in particular the groups CF₃ andC₂ F₅.

When R₉ or R₁₀ represents an alkyl radical having 1 to 20 carbon atomsor an alkenyl radical having from 2 to 20 carbon atoms these may beunderstood as meaning linear or branched radicals optionally substitutedby one or more hydroxyl groups or one or more fluorine atoms.

Amino acid residue may be understood as meaning a residue derived, forexample, from one of the 20 amino acids of L or D configuration (ortheir racemic mixture) constitutive of mammalian proteins.

Sugar residue may be understood as meaning a residue derived, forexample, from glucose, galactose or mannose.

Heterocycle is preferably understood as meaning a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted inposition 4 by a C₁ -C₆ alkyl or mono- or polyhydroxyalkyl radical suchas defined above.

Among the compounds of formula (I) above, the following may especiallybe mentioned:

1)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

2) methyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate;

3)2-hydroxy-4-[2-hydroxyimino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

4)2-acetoxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

5)2-hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

6)2-acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

7)2-hydroxy-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

8)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol;

9) acetate of2-acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol;

10) piperidinylN-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide;

11) morpholinylN-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide;

12)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide;

13)N-ethyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide;

14) methyl2-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoate;

15)2-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoicacid;

16)2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyl]benzoicacid;

17)2-hydroxy-4-[2-hydroxy-2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethoxy]benzoicacid;

18)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]toluene;

19) methyl2,6-dihydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate;

20)2-hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-methoxyphenyl)ethoxy]benzoicacid;

21)2-hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-hydroxyphenyl)ethoxy]benzoicacid;

22) (-) isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

23) (+) isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

24)2-hydroxy-4-[2-hydroxy-2(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

25)2-methoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

26)2-hydroxy-4-[2-hydroxy-2-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)ethoxy]benzoicacid;

27)2-hydroxy-4-[2-amino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;

28)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyloxy]benzoicacid;

29)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hexyloxy]benzoicacid;

30)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5-5,8,8-tetramethyl-2-naphthyl)ethylamino]benzoicacid;

31)2-hydroxy-4-[[2-hydroxy-2-[3-(1-adamantyl)-4-methoxyphenyl]ethoxy]]benzoicacid;

32) 2-hydroxy-4-[[2-[3-(1-adamantyl)-4-methoxyphenyl]ethoxy]]benzoicacid.

The present invention also relates to the processes for the preparationof the compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie) accordingto the reaction schemes described below: ##STR5##

The first step of this preparation comprises reacting in anhydrousmedium in an organic solvent such as DMF a haloketone (1) with a benzylpara-hydroxy-, para-amino- or para-thiosalicylate (2) in the presence ofa tertiary amine (pyridine or triethylamine) or of an alkali metalhydride (sodium hydride) to obtain the compound of formula (3).

The principal step comprises hydrogenating the compound of formula (3)in the presence of a catalyst such as palladium on charcoal in anorganic solvent such as dioxane, methanol or THF.

The hydrogenation can be carried out at a temperature between 20° and60° C. under a hydrogen pressure of between 1 bar and 7 bars and at thesame time allows the free acid to be obtained and the ketonic functionto be reduced.

A hydroxyimino is obtained by the action of hydroxylamine on thecompound (3). The reduction of the hydroxyimino allows the correspondingamine compound to be obtained.

The compounds of general formula (I) where X=(i) can also be prepared byreaction of an acid chloride (5) with an aromatic derivative (4) in thepresence of a Lewis acid (for example AlCl₃) in a chlorinated solventsuch as dichloromethane or dichloroethane or a nitrogenated solvent suchas nitromethane or nitrobenzene. The ketone (6) thus obtained is reducedin alcohol with an alkali metal hydride such as NaBH₄ in an organicsolvent such as THF or ethanol: ##STR6##

The compounds of general formula (I) where X=(ii) can be prepared byreaction of a substituted benzyl bromide (7) with a benzyl alcohol or abenzylamine or a substituted benzyl mercaptan (8) in the presence ofpyridine or of a tertiary amine such as triethylamine in an organicsolvent such as DMF or THF, or in the presence of an alkali metalcarbonate, such as potassium carbonate, in a solvent such as acetone ormethyl ethyl ketone. ##STR7##

The compounds of general formula (I) where X=(iv) can be prepared byreaction of a substituted acetophenone (]) with a substitutedbenzaldehyde (10) in the presence of a base such as sodium hydroxide orsodium methoxide in an alcoholic solvent (ethanol). The chalcone (11)thus obtained is reduced in allyl alcohol (Id) with the aid of an alkalimetal hydride such as NaBH₄ in an alcoholic solvent in the presence of acatalyst (CeCl₃).

Hydrogenation of the compound (Id) in the presence of a catalyst such aspalladium on charcoal in a solvent such as dioxane or methanol givescompounds (Ie) of general formula (I) where X=(iii). ##STR8##

Mitsunobu-type reaction starting from the alcohols (Ib), (Id) or (Ie)gives the azido derivative which can converted into the aminoderivative.

Reaction of an anhydride or of an acid chloride on the amino derivativegives the corresponding amide.

In the case where the radical X is read in the converse manner withrespect to the above schemes resulting in the compounds (Ia), (Ib), (Id)or (Ie), the compounds are obtained by the reactions described in theseschemes using starting materials having the appropriate substituents.

When, in the compounds according to the invention, X represents a di- ortri-hydroxyl radical, these are obtained by epoxidation of thecorresponding ethylenic compounds and opening of the epoxy function inalkaline medium or in the presence of a hydride.

The present invention equally relates by way of medicament to thecompounds of the formula (I) such as described above.

The compounds according to the invention have a good stability to lightand to oxygen.

These compounds exhibit an activity in the embryonic teratocarcinomacell (F9) differentiation test in the mouse (Cancer Research 43, p.5268,1983) and/or in the ornithine decarboxylase inhibition test afterinduction by TPA in the mouse (Cancer Research 38, p.793-801, 1978)and/or on the differentiation of keratinocytes in man (Models Dermatol.Maibach HI, Lowe NJ Ed. Karger Basle (1989)) or in the female rat(Pharmacol. Skin 1989 Vol.3 P. 141-143). These tests show the activityof the compounds in the fields of differentiation and of proliferation.These compounds in addition have a good biological index.

The compounds according the invention are particularly well suited inthe following areas of treatment:

1) For treating dermatological conditions connected with a disorder ofkeratinisation bearing on differentiation and on proliferation,especially for treating common, comedone or polymorphous acne,nodulocystic acne or acne conglobata, senile acne, and secondary acnessuch as solar, drug and occupational acne.

2) For treating other types of keratinisation disorder, especiallyichthyoses, ichthyosiform states, Darier's disease, palmoplantarkeratodermias, leucoplasias and leucoplasiform states, or lichen,cutaneous or mucosal (buccal).

3) For treating other dermatological conditions connected with adisorder of keratinisation with an inflammatory and/or immunoallergiccomponent and, especially, all forms of psoriasis, whether cutaneous,mucosal or unguinal, and even psoriatic rheumatism, or else cutaneousatopy, such as eczema or respiratory atopy or else gingival hypertrophy;the compounds can also be used in certain inflammatory conditions notshowing a keratinisation disorder.

4) For treating all dermal or epidermal proliferations, whether benignor malignant, and whether of viral origin such as common warts, flatwarts and verruciform epidermodysplasia, and oral or florid papillomasand proliferations which may also be induced by ultraviolet rays,especially in the case of basal and prickle cell epitheliomas.

5) For treating other dermatological disorders such as bullousdermatoses and collagen diseases.

6) For treating certain ophthalmological disorders, especiallycorneopathies.

7) For repairing or combating ageing of the skin, be it photoinduced oras a result of time or for reducing pigmentations and actinic keratoses.

8) For preventing or curing epidermal and/or dermal atrophy stigmatainduced by local or systemic corticosteroids, or any other form ofcutaneous atrophy.

9) For preventing or treating healing disorders or for preventing orrepairing vergetures.

10) For combating disorders of the sebaceous function such as thehyperseborrhea of acne or simple seborrhea.

11) In the treatment of cancerous to precancerous states, in particularat the cutaneous level.

12) In the treatment of inflammatory conditions such as arthritis.

The present invention also relates to pharmaceutical compositionscontaining at least one compound of formula (I) such as defined above,or one of its salts.

The present invention thus also relates to a novel pharmaceuticalcomposition intended especially for the treatment of the abovementionedconditions, characterised in that it contains, in a pharmaceuticallyacceptable carrier, at least one compound of formula (I) and/or one ofits salts.

The compounds according to the invention are generally administered in adaily dose of approximately 0.01 mg/kg to 100 mg/kg of body weight in 1to 3 doses.

Administration can be carried out by the enteral, parenteral, topical orocular route. By the enteral route, the medicaments can be present inthe form of tablets, gelatine capsules, coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, microspheres ornanospheres or lipid or polymeric vesicles allowing a controlledrelease. By the parenteral route, the compositions can be present in theform of solutions or suspensions for perfusion or for injection.

By the topical route, the pharmaceutical compositions based on compoundsaccording to the invention are intended for the treatment of the skinand of the mucosa and are present in the form of salved, creams, milks,ointments, powders, moistened pads, solutions, gels, sprays, lotions orsuspensions. They can also be present in the form of microspheres ornanospheres or lipid or polymeric vesicles or polymeric patches andhydrogels allowing a controlled release.

These topical compositions can be present either in anhydrous form or inaqueous form according to the clinical indication.

By the ocular route, these are principally eye lotions.

These compositions contain at least one compound of formula (I) such asdefined above or one of its salts, in a concentration preferably ofbetween 0.001 and 5% with respect to the total weight of thecomposition.

The compounds of formula (I), according to the invention, are also usedin the cosmetic field, in particular in body and hair hygiene andespecially for the treatment of skins with a tendency to acne, for theregrowth of hair, against hair loss, for combating greasiness of theskin or of the hair, in protection against adverse effects of the sun orin the treatment of physiologically dry skins.

The present invention thus also aims at a cosmetic compositioncontaining, in a cosmetically acceptable carrier, at least one compoundof formula (I) or one of its salts, this composition especially beingpresent in the form of a cream, a milk, a lotion, a gel, microspheres ornanospheres or lipid or polymeric vesiculas, a soap or a shampoo.

The concentration of the compound of formula (I) in the cosmeticcompositions is between 0.001 and 3% by weight.

The pharmaceutical and cosmetic compositions according to the inventionmay contain additives which are inert or even pharmacodynamically orcosmetically active, or combinations of these, and especially: wettingagents, depigmenting agents such as hydroquinone, azelaic acid, caffeicacid or kojic acid, emollients, hydrating agents such as glycerol, PEG400, thiamorpholinone and its derivatives or urea; antiseborrheic orantiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine,their salts and their derivatives, tioxolone or benzoyl peroxide;antibiotics such as erythromycin and its esters, neomycin, chindamycinand its esters tetracyclines, antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolinones; agents promoting the regrowth ofthe hair, such as "minoxidil"(2,4-diamino-6-piperidinopyrimidine-3-oxide) and its derivatives,diazoxide (7-chloro-3-methyl- 1,2,4-benzothiadiazine-1,1-dioxide) andphenytoin (5,5-diphenylimidazolidine-2,4-dione); steroidal andnon-steroidal anti-flammatory agents; carotenoids and, especially,β-carotene; anti-psoriatic agents such as anthralin and its derivativesand eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, theiresters and amides.

The compositions according to the invention may also containflavour-enhancing agents, preservatives such as the esters ofpara-hydroxybenzoic acid, stabilisers, humidity-regulating agents,pH-regulating agents, osmotic pressure-modifying agents, emulsifyingagents, UV-A and UV-B filters, and antioxidants such as α-tocopherol,butylhydroxyanisole or butylhydroxytoluene.

Several examples of preparation of the active compounds of formula (I)according to the invention and also examples of compositions containingthem will now be given by way of illustration and without any limitingcharacter.

A. EXAMPLES OF COMPOUNDS EXAMPLE 12-Hydroxy-4-[2-hydroxy,2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid.

(a) Benzyl 2,4-dihydroxybenzoate:

15.4 g (0.1 mol) of 2,4-dihydroxybenzoic acid dissolved in 50 ml of DMFare added dropwise to a solution of 3 g (0.1 mol) of sodium hydride (80%in oil) and 50 ml of DMF and the mixture is stirred at room temperatureuntil evolution of gas has ceased. 13.1 ml (0.1 mol) of benzyl bromideare then added and the mixture is stirred at room temperature until thereaction mixture has dissolved. The reaction mixture is poured intowater and extracted with ethyl ether, and the organic phase isseparated, washed with water, dried over magnesium sulphate andevaporated. The residue is purified by chromatography on a silicacolumn, eluting with dichloromethane. 19.7 g (81%) of the expected esterare collected, which melts at 94°-95° C.

(b)2-(2'-Bromoacetyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene):

3.5 g (15.2 mmol) of2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 25 ml ofethyl ether and 25 ml of dioxane are introduced into a flask. 810 μl(15.2 mmol) of bromine are added dropwise and the mixture is stirred atroom temperature for one hour. The reaction mixture is poured into waterand extracted-with ethyl ether, and the organic phase is separated,dried over magnesium sulphate and evaporated. The residue obtained ispurified by chromatography on a silica column, eluted with a mixture ofdichloromethane and hexane (30-70). After evaporation of the solvents,3.5 g (74%) of bromo derivative are collected, in the form of slightlyyellow crystals, melting at 61°-62° C.

(c) Benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate:

300 mg (10 mmol) of sodium hydride (80% in oil) and 25 ml of DMF areintroduced into a flask. A solution of 2.4 g (10 mmol) of benzyl2,4-dihydroxybenzoate in 75 ml of DMF is added dropwise and the mixtureis stirred until evolution of gas has ceased. A solution of 3.1 g (10mmol) of the bromo derivative prepared above in 50 ml of DMF is thenadded and the mixture is stirred at room temperature for 2 hours. Thereaction mixture is poured into water and extracted with ethyl ether,and the organic phase is separated, dried over magnesium sulphate andevaporated. The residue obtained is purified by chromatography on asilica column, eluted with a mixture of dichloromethane and hexane(50:50). After evaporation of the solvents, 3.4 g (73%) of the expectedproduct are obtained, which melts at 103°-104° C.

(d)2-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-]2-naphthyl)ethoxybenzoic acid:

2.9 g (6.1 mmol) of the ester prepared above, 1 g of palladium oncharcoal (10%) and 100 ml of dioxane are introduced into a reactor. Themixture is hydrogenated at room temperature and under a pressure of 7bar for 4 hours, the catalyst is filtered and washed twice with 50 ml ofTHF each time, and the filtrates are evaporated. The residue obtained ispurified by chromatography on a silica column, eluting with a mixture ofdichloromethane and ethyl ether (95:5). After evaporation of thesolvents, 2 g (87%) of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy-benzoicacid which melts at 206°-207° C. are collected.

EXAMPLE 2 Methyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate.

(a) Methyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8-8-tetramethyl-2-naphthoylmethoxy)benzoate:

990 mg (33 mmol) of sodium hydride (80% in oil) and 50 ml of DMF areintroduced in a flask. A solution of 5.6 g (33 mmol) of methyl2,4-dihydroxybenzoate in 50 ml of DMF is added dropwise under a currentof nitrogen and the mixture is stirred until evolution of gas hasceased. A solution of 9.4 g (33 mmol) of bromoketone prepared in 1(b)dissolved in 75 ml of DMF is then introduced dropwise and the mixture isstirred at room temperature for 2 hours. The reaction mixture is pouredinto water and extracted with ethyl ether, and the organic phase isseparated, dried over magnesium sulphate and evaporated. The residueobtained is purified by chromatography on a silica column, eluted with amixture of dichloromethane and hexane (70:30). After evaporation of thesolvents, 8.5 g (72%) of the expected ester which melts at 113°-114° C.are collected.

(b) Methyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate:

1.6 g (4 mmol) of the ketone prepared above, 50 ml of THF and 50 ml ofmethanol are introduced into a flask. 80 mg (2 mmol) of sodiumborohydride are added in small quantities and the mixture is stirred atroom temperature for 2 hours. The reaction mixture is evaporated todryness, the residue is taken up with water and ethyl ether, and theorganic phase is separated, dried over magnesium sulphate andevaporated. The solid obtained is triturated in hexane, filtered anddried in vacuo. 1.6 g (100%) of the expected product which melts at133°-134° C. are collected.

EXAMPLE 32-Hydroxy-4-[2-hydroxyimino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

(a) Methyl2-hydroxy-4-[2-hydroxyimino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate.

6.6 g (16.6 mmol) of methyl2-hydro-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate, 200 ml of ethanol and 4.6 g (66.6 mmol) of hydroxylaminehydrochloride are introduced into a flask. 66 ml of sodium hydroxide(iN) are added dropwise and the mixture is heated to reflux for 2 hours.It is evaporated to dryness, the residue is taken up with water andethyl ether, and the organic phase is separated, dried over magnesiumsulphate and evaporated. The residue obtained is purified bychromatography on a silica column, eluted with dichloromethane. Afterevaporation of the solvents, 4.4 g (64%) of the syn isomer which meltsat 138°-9° C. and 1.9 g (30%) of the anti isomer which melts at165°-166° C. are obtained.

(b)2-Hydroxy-4-[2-hydroxyimino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid:

2.05 g (5 mmol) of the above syn isomer, 50 ml of THF and 50 ml of 2Nmethanolic sodium hydroxide are introduced into a flask. The mixture isheated to reflux for 8 hours, the reaction mixture is evaporated, theresidue is taken up with water, and the mixture is neutralised withconcentrated hydrochloric acid and extracted with ethyl ether. Theorganic phase is separated, dried over magnesium sulphate andevaporated. The residue obtained is triturated in dichloromethane andfiltered. 1.6 g (81%) of the expected product which melts at 220°-222°C. with decomposition are obtained.

EXAMPLE 42-Acetoxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

(a) Benzyl 2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate.

5 g (10.5 mmol) of benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate,50 ml of THF and 50 ml of methanol are introduced into a flask. 200 mg(5.3 mmol) of sodium borohydride are added in small quantities and thereaction mixture is stirred at room temperature for 1 hour. It isevaporated to dryness, the residue is taken up with water and ethylether, and the organic phase is separated, dried over magnesium sulphateand evaporated. 5 g (100%) of the expected product are collected in theform of a slightly yellow oil.

(b) Benzyl2-acetoxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate:

4.8 g (10 mmol) of the above product, 50 ml of THF and 4.2 ml (30 mmol)of triethylamine are introduced into a flask. 2.2 ml (30 mmol) of acetylchloride are added dropwise and the reaction mixture is stirred at roomtemperature for 8 hours. It is poured into water and extracted withethyl ether, and the organic phase is separated, dried over magnesiumsulphate and evaporated. The residue obtained is purified bychromatography on a silica column, eluted with dichloromethane. Afterevaporation of the solvents, 3.8 g (76%) of the expected product arecollected in the form of an oil.

(c)2-Acetoxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid:

1.5 g (2.7 mmol) of the above product, 200 ml of dioxane and 300 mg ofPd/C (10%) are introduced into a reactor. The mixture is hydrogenated atroom temperature and under a pressure of 7 bar for 2 hours. The catalystis filtered and washed twice with 50 ml of THF each time and thefiltrates are evaporated. The residue obtained is triturated in amixture of hexane and ethyl ether (90:10), filtered and dried in vacuo.1.2 g (92%) of the expected product which melts at 88°-89° C. arecollected.

EXAMPLE 52-Hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl1-2-naphthyl)ethoxy]benzoicacid

(a) Benzyl2-hydroxy-4-[2-acetoxy-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

2.2 g (4.6 mmol) of benzyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate,50 ml of THF and 380 μl (4.6 mmol) of pyridine are introduced into aflask. 330 μl (4.6 mmol) of acetyl chloride are added dropwise and thereaction mixture is stirred at room temperature for 8 hours. It ispoured into water and extracted with ethyl ether, and the organic phaseis separated, dried over magnesium sulphate and evaporated. The residueobtained is purified by chromatography on a silica column, eluted with amixture of hexane and dichloromethane (90:10). After evaporation of thesolvents, 1.8 g (77%) of the expected product are collected in the formof a yellow oil.

(b)2-Hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

Starting from 1.5 g (2.9 mmol) of the above product in a manneranalogous to Example 4(c), 1.1 g (90%) of the expected product whichmelts at 160°-161° C. are obtained.

EXAMPLE 62-Acetoxy-4-[2-hydroxy-2,(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

(a) Benzyl2-acetoxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate

By reaction of 2.36 g (5 mmol) of benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoateand 360 μl (5 mmol) of acetyl chloride in a manner analogous to Example4(b), 2 g (80%) of the expected product which melts at 137°-138° C. arecollected.

(b)2-Acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

Starting from 1.9 g (3.7 mmol) of the above product in a manneranalogous to Example 1(d), 1.4 g (89%) of the expected product whichmelts at 119°-120° C. are obtained.

EXAMPLE 72-Hydroxy-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

2 g (3.89 mmol) of benzyl2-hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoateobtained in Example 5(a), 100 ml of ethanol, 10 ml of acetic acid and1.2 g of palladium on charcoal (10% to 50% water) are introduced into areactor. The mixture is hydrogenated at 70° C., under a pressure of 7bar, for 4 hours. The catalyst is filtered and washed with ethanol, andthe filtrate is evaporated. The residue obtained is taken up in hexane,filtered and dried. 650 mg (46%) of the expected product of meltingpoint 210°-212° C. are obtained.

EXAMPLE 82-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol

1.27 g (2.68 mmol) of benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoateand 15 ml of THF are introduced into a flask. 480 mg (12 mmol) of LiAlH₄(96%) are added in small quantities. The mixture is stirred at roomtemperature for 15 minutes. Hydrated Na₂ SO₄ is added in smallquantities. The mixture is stirred at room temperature overnight. Theinsoluble matter is filtered, and the filtrate is washed with THF andevaporated. The residue obtained is purified by chromatography on asilica column, eluted with a hexane/ethyl acetate mixture (60:40). Afterevaporation of the solvents, 260 mg (26%) of the expected product arecollected in the form of a oil which crystallises slowly at roomtemperature, of melting point 110°-115° C.

EXAMPLE 92-Acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol acetate

1.2 g (3.23 mmol) of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)ethoxy]benzylalcohol and 30 ml of pyridine are introduced into a flask and 345 ml(4.84 mmol) of acetyl chloride are added. The reaction mixture isstirred at 0° C. for 4 hours. It is poured into water, acidified withhydrochloric acid and extracted with ethyl acetate. The extract iswashed with water, and the organic phase is separated, dried over sodiumsulphate and evaporated. The residue obtained is purified bychromatography on a silica column, eluted with a mixture of hexane andethyl acetate (70:30). After evaporation of the solvents, 140 mg (10.4%)of the expected product are collected in the form of a pale yellow oil.

EXAMPLE 10N-piperidinyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide

3.43 g (7.6 mmol) ofN-piperidinyl-2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamide,100 ml of isopropanol and 50 ml of THF are introduced into a flask. Themixture is cooled to 0° C. and 144 mg (3.81 mmol) of NaBH₄ are added.The mixture is stirred at 0° C. for 1 hour. Acetone is added, thesolvents are evaporated, the residue is taken up in water and themixture is adjusted to pH 6-7 with hydrochloric acid (1N). The mixtureis extracted with ethyl acetate, washed with water and dried over sodiumsulphate, and the solvents are evaporated. The residue obtained ispurified by chromatography on a silica column eluted with a mixture ofethyl acetate and hexane (35:65). After evaporation of the solvents, theoil obtained is crystallised in hexane, filtered and dried, and 4.25 g(86%) of the expected product of melting point 124° C. are collected.

EXAMPLE 11N-Morpholinyl1-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide

Starting from 5.5 g (12 mmol) ofN-morpholinyl-2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamidein a manner analogous to Example 10 and by recrystallisation in 10volumes of ethanol, 4.24 g (77%) of the expected product of meltingpoint 153° C. are collected.

EXAMPLE 122-Hydroxy-4-[2-hydroxy-2-(5,6,7,8,tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide

Starting from 4.4g (11 mmol) of2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamidein a manner analogous to Example 10, a yellow oil is obtained whichcrystallises in a mixture of ethanol/water. After filtration and drying,3.72 g (84%) of the expected product of melting point 85°-90° C. arecollected.

EXAMPLE 13N-Ethyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide

Starting from 2.4 g (5.87 mmol) ofN-ethyl-2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamidein a manner analogous to Example 10, a yellow oil is obtained whichcrystallises in hexane. After filtration and drying, 2.24 g (93%) of theexpected product of melting point 65°-70° C. are collected.

EXAMPLE 14 Methyl2-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoate

a) 6-(2-Bromoacetyl)-4,4-dimethylthiochroman

In a manner analogous to Example 1(b), the synthesis is carried outstarting from 1 g (4.42 mmol) of 6-acetyl-4,4-dimethylthiochroman and700 mg (4.42 mmol) of bromine. After treatment and purification bychromatography on a silica column, eluting with a mixture ofdichloromethane/hexane (40:60), 700 mg (53%) of expected bromoderivative are obtained in the form of a chestnut-brown oil.

b) Methyl 2-hydroxy-4-(4,4-dimethylthiochroman-6-oyl-methoxy)benzoate

5 ml of dimethylformamide and 80 mg (2.75 mmol) of 80% sodium hydrideare poured into a 100 ml three-necked flask, under nitrogen. 430 mg(2.57 mmol) of methyl 2,4-dihydroxybenzoate dissolved in 20 ml ofdimethyl-formamide are introduced dropwise at room temperature and themixture is stirred until evolution of hydrogen has ceased. 770 mg (2.57mmol) of bromo derivative obtained above dissolved in 15 ml ofdimethylformamide are then added. The mixture is stirred at roomtemperature for 5 hours, poured into water and extracted with ethylether, and the extract is dried over sodium sulphate. After filtration,the solvents are evaporated and 1 g of crude product is recovered whichis chromatographed on a silica column, eluting with dichloromethane. 540mg (53%) of expected product of melting point 135°-137° C. are thusobtained.

c) Methyl2-hydroxy-4-[2-hydroxy-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoate

540 mg (1.4 mmol) of the derivative obtained above dissolved in 15 ml ofTHF are introduced into a 50 ml"three-necked flask, under nitrogen. 50mg (1.4 mmol) of sodium borohydride are added. After reacting for 30minutes at room temperature, the reaction mixture is poured into waterand extracted with ethyl acetate, the extract is dried over sodiumsulphate and filtered, and the organic phase is evaporated to dryness.530 mg of expected product, crystallising in hexane, of melting point113°-115° C. are obtained.

EXAMPLE 152-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoicacid

450 mg (1.16 mmol) of the above derivative and 10 ml of methanol areintroduced into a 100 ml flask, and 460 mg (11.6 mmol) of sodiumhydroxide are added as pellets. The mixture is heated under reflux for12 hours, the solvent is evaporated and the residue is taken up withwater. The mixture is acidified and extracted with ethyl acetate, andthe organic phase is dried over sodium sulphate, filtered and evaporatedto dryness. 500 mg of a chestnut-brown oil are recovered, which ischromatographed on a silica column, eluting with ethyl acetate. Afterevaporation of the solvent, the residue is triturated in hexane andfiltered. 210 mg (49%) of expected acid of melting point 166°-167° C.are thus obtained.

EXAMPLE 162-Hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyl]benzoicacid

a)2-Hydroxy-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]benzoicacid

2.3 g (10 mmol) of2-aceto-5,6,7,7,8-tetrahydro-5,5,8,8-tetramethylnaphthone, 1.8 g (10mmol) of methyl 2-hydroxy-4-formylbenzoate, 70 ml of methanol and 40 mlof sodium hydroxide (1N) are introduced into a flask. The mixture isstirred at room temperature for 24 hours and evaporated to dryness, theresidue is taken up with water, the mixture is acidified withhydrochloric acid and extracted with ethyl ether, and the organic phaseis separated, dried over sodium sulphate and evaporated. The residue isrecrystallised in ethyl alcohol, and the crystals are filtered anddried. 1.5 g (41%) of the expected product of melting point 260°-261° C.are collected.

b)2-Hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyl]benzoicacid

1.5 g (4 mmol) of the above acid are hydrogenated at room temperatureand under a pressure of 7 bar in 60 ml of dioxane in the presence of 550mg of 10% palladium on charcoal for 4 hours. After filtration andevaporation of the filtrate, the residue obtained is triturated inhexane and filtered. 870 mg (57%) of the expected product of meltingpoint 144°-145° C. are collected.

EXAMPLE 17 2-Hydroxy-4-[2-hydroxy-2-(3,5-di-tert-butyl1-4-hydroxyphenyl)ethoxy]benzoic acid

a) 3,5-Di-tert-butyl-4-hydroxy-2'-bromoacetophenone

Starting from 2.5 g (10 mmol) of3,5-di-tert-butyl-4-hydroxy-acetophenone, analogously to Example 1(b),1.6 g (48%) of bromo derivative are collected in the form of a slightlyyellow oil.

b) Benzyl2-hydroxy-4-(3,5-di-tert-butyl-4-hydroxybenzoylmethoxy)benzoate

By reaction of 1.6 g (4.9 mmol) of the above bromo derivative with 1.2 g(4.9 mmol) of benzyl 2,4-dihydroxybenzoate in a manner analogous toExample 19(a), 2 g (83%) of the expected ester of melting point122°-123° C. are obtained.

c) 2-Hydroxy-4-[(3,5-di-tert-butyl-4-hydroxybenzoyl)methoxy]benzoic acid

1.5 g (3.06 mmol) of the above ester, 60 ml of dioxane and 300 mg of 10%palladium on charcoal are introduced into a reactor. The mixture ishydrogenated at room temperature and under a pressure of 7 bar for 1hour, the catalyst is filtered and the filtrate is evaporated. Theresidue obtained is triturated in hexane, filtered and dried. 1 g (82%)of the expected product of melting point 164°-165° C. is collected.

d)2-hydroxy-4-[2-hydroxy-2-(3,5-di-tert-butyl-4hydroxyphenyl)ethoxy]benzoicacid

Starting from 1 g (2.5 mmol) of the above ester in a manner analogous toExample 2(b), 710 mg (71%) of the expected product of melting point132°-133° C. are obtained.

Example 182-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]toluene

a)2-Hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzaldehyde

By reaction of 6.2 g (20 mmol) of2'-bromoaceto)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthone with 2.8g (20 mmol) of 2,4-dihydroxybenzaldehyde in a manner analogous toExample 19(a), 6.9 g (94%) of expected aldehyde are obtained in the formof a colourless oil.

b)2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]toluene

1 g (2.7 mmol) of the above aldehyde is hydrogenated at room temperatureand under a pressure of 7 bar in the presence of 200 mg of 10% palladiumon charcoal. After filtration, and evaporation of the filtrate, theresidue obtained is purified by chromatography on a silica column,eluting with a mixture of ethyl ether/hexane (30:70). 600 mg (62%) ofthe expected product of melting point 120°-121° C. are collected.

Example 19 Methyl2,6-dihydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

a) Methyl2,6-dihydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate

3.1 g (10 mmol) of2-(2'-bromoaceto)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthone, 1.8 g(10 mmol) of methyl 2,4,6-trihydroxybenzoate, 1.4 g (10 mmol) ofpotassium carbonate and 100 ml of methyl ethyl ketone are introducedinto a flask. The mixture is heated under reflux for 1 hour andevaporated to dryness. The residue is taken up with water anddichloromethane, and the organic phase is separated, dried overmagnesium sulphate and evaporated. The residue obtained is purified bychromatography on a silica column, eluted with a mixture ofdichloromethane and hexane (50:50). After evaporation of the solvents,2.2 g (53%) of the expected product of melting point 169°-170° C. arecollected.

b) Methyl2,6-dihydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

Starting from 2.7g (6.5 mmol) of the above ester in a manner analogousto Example 2(b), 2.1 g (77%) of the expected product of melting point127°-128° C. are obtained.

EXAMPLE 202-Hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-methoxyphenyl)ethoxy]benzoicacid

a) 3-tert-Butyl-4-methoxyacetophenone 22.6 g (0.1 mol) of3-tert-butyl-4-methoxybenzoyl chloride, 30 ml of HMPA, 14 ml (0.1 mol)of tetramethyltin and 43 mg ofbenzyl(chloro)bis(triphenylphosphine)palladium(II) are introduced into athree-necked flask under a stream of nitrogen. The mixture is heated at80° C. for 4 hours, poured into water and extracted with ethyl ether,and the organic phase is separated, dried over magnesium sulphate andevaporated. The residue obtained is purified by chromatography on asilica column, eluted with a mixture of dichloromethane/hexane (50:50).After evaporation of the solvents, 11.5 g (58%) of the expected ketoneof melting point 68°-69° C. are collected.

b) 3-tert-Butyl-4-methoxy-(2'-bromo)acetophenone

Starting from 8.24 g (40 mmol) of the ketone obtained in 20(a), in amanner analogous to Example 1(b), 8.7 g (76%) of bromo derivative areobtained in the form of a slightly yellow oil.

c) Benzyl 2-hydroxy-4-[3-tert-butyl-4-methoxybenzoyl)methoxy]benzoate

By reaction of 8.7 g (30 mmol) of the above bromo derivative with 7.5 g(30 mmol) of benzyl 2,4-dihydroxybenzoate in a manner analogous toExample 19(a), 11 g (80%) of the expected ester of melting point 98°-99°C. are obtained.

d)2-Hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-methyoxyphenyl)ethoxy]benzoicacid

Staring from 5 g (11.2 mmol) of ally2-hydroxy-4-(3-tert-butyl-4-methoxybenzoylmethoxy)benzoate in a manneranalogous to Example 1(d), 4 g (99%) of expected acid of melting point149°-150° C. are obtained.

EXAMPLE 212-Hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-hydroxyphenyl)ethoxy]benzoicacid

a) Methyl 3-tert-butyl-4-benzyloxybenzoate By reaction of 17 g (82 mmol)of methyl 3-tert-butyl-4-hydroxybenzoate with 10.7 ml (82 mmol) ofbenzyl bromide in a manner analogous to Example 1(a), 24.4 g (100%) ofthe expected product are obtained in the form of a colourless oil.

b) 3-tert-Butyl-4-benzyloxybenzoic acid 24.4 g (82 mmol) of the aboveester and 400 ml of 1N methanolic sodium hydroxide are introduced into aflask. The mixture is heated to reflux for 3 hours and evaporated todryness, and the residue is taken up with water, acidified to pH=1 andextracted with ethyl ether, and the organic phase is separated, driedover magnesium sulphate and evaporated. The residue obtained istriturated in hexane, filtered and dried. 21 g (85%) of expected acid ofmelting point 213°-214° C. are collected.

c) 3-tert-butyl-4-benzyloxyacetophenone

By reaction of 10 g (35 mmol) of the above acid with 5 ml (35 mmol) oftetramethyltin in the presence ofbenzyl(chloro)bis(triphenylphosphine(palladium(II) in a manner analogousto Example 20(a), 5.8 g (58%) of the expected ketone are obtained in theform of a colourless oil.

d) 3-tert-Butyl-4-methoxy-(2'-bromo)acetophenone

Starting from 5.8 g (20 mmol) of the ketone obtained in 21(c), in amanner analogous to Example 1(b), 4.6 g (62%) of the expected bromoderivative are obtained in the form of a slightly yellow oil.

e) Benzyl 2-hydroxy-4-[(3-tert-butyl-4-benzyloxybenzoyl)methoxy]benzoate

By reaction of 4.6 g (13 mmol) of the above bromo derivative with 3.1 g(13 mmol) of benzyl 2,4-dihydroxybenzoate in a manner analogous toExample 19(a), 5.4 g (81%) of the expected ester of melting point91°-93° C. are obtained.

f) 2-Hydroxy-4-[2-hydroxy-2-(3-tert-butyl-4-hydroxyphenyl)ethoxy]benzoicacid

By hydrogenation of 2 g (3.8 mmol) of the above ester in the presence of1.5 g of 10% palladium on charcoal in a manner analogous to Example1(d), 1.9 g (90%) of the expected acid of melting point 96°-97° C. areobtained.

EXAMPLE 22 (-)-Isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

a) Benzyl2-(2-methoxyethoxymethoxy)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate

1.65 g (55 mmol) of sodium hydride (80% in oil) and 50 ml of DMF areintroduced into a flask. A solution of 23.6 g (50 mmol) of allyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate in 200 ml of DMF is added dropwise and the mixture isstirred until evolution of gas has ceased. 6.3 ml (55 mmol) of 2-methoxyethoxymethyl chloride are then added dropwise and the reaction mixtureis stirred for 2 hours. It is poured into water and extracted with ethylether, and the organic phase is separated, dried over magnesium sulphateand evaporated. The residue obtained is purified by chromatography on asilica column, eluted with a mixture of dichloromethane/ethyl ether(98:2). After evaporation of the solvents, 19.2 g (69%) of the expectedester are collected in the form of a slightly yellow oil.

b) Benzyl2-(2-methoxyethoxymethoxy)-4-(2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

Starting from 10.3 g (18.3 mmol) of the above ester in a manneranalogous to Example 2(b), 8.7 g (85%) of the expected product areobtained in the form of a yellow oil.

c) Benzyl2(2-methoxyethoxymethoxy)-4-[2-(R)-α-methoxyphenylacetoxy-2-(5,6,7,8-teytrahydro-5,5,8,8tetramethyl-2-naphthyl)ethoxy]benzoate

10.5 g (18.6 mmol) of allyl2-(2-methoxyethoxymethoxy)-4-(2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate,3.1 g (18.6 mmol) of (R)-(-)α-methoxyphenylacetic acid and 100 ml ofdichloromethane are introduced into a flask. 3.8 g (18.6 mmol) ofdicyclohexylcarbodiimide and 2.3 g (18.6 mmol) of4-dimethylaminopyridine are added successively and the reaction mixtureis stirred at room temperature for 4 hours. It is poured into water andextracted with ethyl ether, and the organic phase is separated, driedover magnesium sulphate and evaporated. The two diastereoisomers formedare separated by chromatography on a silica column, eluting with amixture of hexane/ethyl ether (55:45). After evaporation of the solventsthe following are collected:

5 g (38%) of the (-)-diastereoisomer in the form of a slightly yellowoil:

    [α].sub.D.sup.22 =-43.1°(c=1, CH.sub.2 Cl.sub.2)

4.8 g (36%) of the (+)-diastereoisomer in the form of a slightly yellowoil:

    [α].sub.D.sup.22 =+10.8°(c=1, CH.sub.2 Cl.sub.2)

d) (-)-Diastereoisomer of benzyl2-hydroxy-4-[2-(R)-α-methoxyphenylacetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

2.5 g (3.5 mmol) of the (-)-diastereoisomer prepared in Example 22(c)and 100 ml of dichloromethane are introduced into a flask. 270 mmol) oftrifluoroacetic acid are added dropwise and the mixture is stirred for15 min. It is poured into water and extracted with ethyl ether, and theorganic phase is separated, dried over magnesium sulphate andevaporated. The residue is purified by filtration on silica, in amixture of dichloromethane/hexane (90:10). After evaporation of thesolvents, 2.1 g (97%) of the expected ester are collected in the form ofa yellow oil:

    [α].sub.D.sup.22 =-45.1°(c=1, CH.sub.2 Cl.sub.2)

e) (-)-Isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

Starting from 2 g (3.2 mmol) of the above ester in a manner analogous toExample 3(c), 1.1 g (92%) of the expected (-)-acid of melting point199°-200° C. are obtained.

    [α].sub.D.sup.20 =-7.6° (c=1,DMF)

EXAMPLE 23 (+)-Isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

a) (+)-Diastereoisomer of benzyl2-hydroxy-4-[2-(R)-α-methoxyphenylacetoxy-2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

Starting from 4.4 g (6.3 mmol) of the (+)-diastereoisomer obtained inExample 22(c) in a manner analogous to Example 22(d), 3.7 g (95%) of theexpected ester are collected in the form of a yellow oil:

    [α].sub.D.sup.22 =+19.5°(c=1, CH.sub.2 Cl.sub.2)

b) (+)-Isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-2-naphthyl)ethoxy]benzoicacid

Staring from 3.5 g (5.6 mmol) of the above ester in a manner analogousto Example 22(e), 1.8 g (86%) of the expected (+)-acid of melting point199°-200° C. are obtained:

    [α].sub.D.sup.20 =+7.5°(c=1,DMF)

EXAMPLE 242-Hydroxy-4-[2-hydroxy-2(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

a) 3-Methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetonaphthone

990 mg (33 mmol) of sodium hydride (80% in oil) and 20 ml of DMF areintroduced into a flask. A solution of 6.8 g (27.6 mmol) of3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetonaphthone in 75ml of DMF are added dropwise under a stream of nitrogen and the mixtureis stirred until evolution of gas has ceased. 2.1 ml (33 mmol) ofiodomethane are then added with cooling and the mixture is stirred atroom temperature for 2 hours. It is then poured into water and extractedwith ethyl ether, and the organic phase is separated, dried overmagnesium sulphate and evaporated. The residue obtained is purified bychromatography on a silica column, eluted with a mixture ofdichloromethane/hexane (40:60). After evaporation of the solvents, 6 g(84%) of the expected product of melting point 104°-105° C. arecollected.

b)2-(2'-Bromoaceto)-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthone

Staring from 5.7 g (21.9 mmol) of the above ketone in a manner analogousto Example 1(b), 7.4 g (100%) of expected bromo derivative of meltingpoint 99°-100° C. are obtained.

c) Benzyl2-hydroxy-4-[3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate

By reaction of 7.4 g (21.9 mmol) of the above bromo derivative with 5.4g (22 mmol) of benzyl 2,4-dihydroxybenzoate in a manner analogous toExample 19(a), 8.1 g (74%) of the expected ester of melting point118°-119° C. are obtained.

d)2-Hydroxy-4-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoicacid

Starting from 1 g (2 mmol) of the above benzyl ester in a manneranalogous to Example 18(c), 640 mg (78%) of the expected acid of meltingpoint 200°-201° C. are obtained.

e)2-Hydroxy-4-[2-hydroxy-2(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

Staring from 1 g (2 mmol) of the above acid in a manner analogous toExample 2(a), 580 mg (70%) of the expected product of melting point178°-179° C. are obtained.

EXAMPLE 252-Methoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

a) Benzyl2-methoxy-4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethoxy)benzoate

By reaction of 1.9 g (4 mmol) of benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoxylmethoxy)benzoatewith 280 ml (4.4 mmol) of iodomethane in a manner analogous to Example1(a), 1.8 g (93%) of the expected product of melting point 112°-113° C.are obtained.

b)2-Methoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

Starting from 1.7 g (3.5 mmol) of the above benzyl ester in a manneranalogous to Example 1(d), 1.1. g (79%) of the expected acid of meltingpoint 150°-151° C. are obtained.

EXAMPLE 262-Hydroxy-4-[2-hydroxy-2-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxybenzoicacid

a) Benzyl2-hydroxy-4(3-hydroxy-5,6,7,8,-teytrahydro-5,5,8,8-tetrameythyl-2-naphthoylmethoxy)benzoate4 g (8 mmol) of benzyl2-hydroxy-4-(3-methoxy-5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthoxylmethoxy)benzoateand 20 ml of dichloromethane are introduced into a flask. 24 ml (24mmol) of a solution of boron trichloride in THF (1M) are added dropwiseat -78° C. and under a stream of nitrogen and the temperature is allowedto rise to -20° C., then the reaction mixture is poured into ice-water.The mixture is extracted with ethyl ether, and the organic phase isseparated, dried over magnesium sulphate and evaporated. The residueobtained in purified by chromatography on a silica column, eluted with adichloromethane/hexane mixture (50:50). 3.1 g (80%) of the expectedester of melting point 127°-128° C. are obtained.

b)2-Hydroxy-4-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoxylmethoxy)benzoicacid

Starting from 2.8 g (5.7 mmol) of the above benzyl ester in a manneranalogous to Example 17(c), 2 g (88%) of the expected acid which meltsat 194°-195° C. are obtained.

c)2-Hydroxy-4-[2-hydroxy-2-(3-hydroxy-5,6,7,8tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]acid

Starting from 1 g (2.5 mmol) of the acid obtained in 26(b) in a manneranalogous to Example 2(b), 270 mg (27%) of expected acid of meltingpoint 110°-111° C. are obtained.

EXAMPLE 272-Hydroxy-4-[2-amino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

a) Benzyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

Starting from 9.44 g (20 mmol) of benzyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoatein a manner analogous to Example 2(b), 9/4 g (100%) of the expectedester are obtained in the form of a slightly yellow oil.

b) Benzyl2-hydroxy-4-[2-methanesulphonyloxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

1.8 g (3.8 mmol) of the above ester, 920 ml (11.4 mmol) of pyridine and100 ml of dichloromethane are introduced into a flask. A solution of 350ml (4.6 mmol) of methanesulphonyl chloride in 50 ml of dichloromethaneis added dropwise at 0° C. and the mixture is stirred at roomtemperature for 4 hours. It is evaporated to dryness, the residue istaken up with ethyl ether, and the organic phase is washed with water,dried over magnesium sulphate and evaporated. 2.1 g (100%) of theexpected product are collected in the form of an oil.

c) Benzyl2-hydroxy-4-[2-azido-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

2.1 g (3.8 mmol) of the ester obtained in 27(b), 50 ml of DMF and 750 mg(11.4 mmol) of sodium azide are introduced into a flask. The reactionmixture is stirred at room temperature for 12 hours, poured into waterand extracted with ethyl ether, and the organic phase is separated,dried over magnesium sulphate and evaporated. The residue obtained ispurified by chromatography on a silica column, eluted with adichloromethane/hexane mixture (40:60). After evaporation of thesolvents, 1.2 g (67%) of the expected product are collected in the formof a colourless oil.

d) Benzyl2-hydroxy-4-[2-amino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate

2.2 g (4.4 mmol) of the above ester, 1.2 g (4.4 mmol) oftriphenylphosphine, 120 ml (6.6 mmol) of water and 100 ml of THF areintroduced into a flask. The mixture is stirred at room temperature for24 hours and evaporated to dryness, and the residue is chromatographedon a silica column eluting with a hexane/ethyl ether mixture (40:60).After evaporation of the solvents, 1 g (48%) of the expected product iscollected in the form of a slightly yellow oil.

e)2-Hydroxy-4-[2-amino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid

800 mg (1.7 mmol) of the above ester and 30 ml of a 2N methanolic sodiumhydroxide solution are introduced into a flask. The reaction mixture isheated under reflux for 4 hours and evaporated, the residue is taken upwith water, and the mixture is neutralised to pH=5 with 1N hydrochloricacid and extracted with ethyl ether. The organic phase is separated,washed with water, dried over magnesium sulphate and evaporated. Theresidue is triturated in the minimum of ethyl ether, filtered and dried.110 g (17%) of the expected product of melting point 241°-242° C. arecollected.

EXAMPLE 282-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyloxy]benzoicacid

1 g (2.6 mmol) of2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoicacid and 50 ml of THF are introduced into a three-necked flask under astream of nitrogen. 5.3 ml (8.3 mmol) of a solution of methyl lithium inTHF (1.6M) are added dropwise at -78° C. and the reaction mixture isstirred for 12 hours at room temperature. It is poured into ice-water,acidified to pH=1 and extracted with ethyl ether, and the organic phaseis separated, dried over magnesium sulphate and evaporated. The residueobtained is recrystalised in cyclohexane and 900 mg (86%) of theexpected product of melting point 170°-171° C. are collected.

EXAMPLE 292-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hexyloxy]benzoicacid

By reaction of 1.1 g (2.9 mmol) of2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethoxy)benzoicacid with 5.4 ml (8.6 mmol) of a solution of n-butyllithium (1.6M) inhexane in a manner analogous to Example 28, 140 mg (11%) of expectedacid of melting point 142°-143° C. are obtained.

EXAMPLE 302-Hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethylamino]benzoicacid

2.05 g (5 mmol) of methyl2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylcarboxamido)bezoateand 50 ml of dioxane are introduced into a flask. 1.9 g (50 mmol) ofsodium borohydride are added in small quantities and the mixture isstirred for 30 min at room temperature. It is cooled to 0° C. and 2.9 ml(50 mmol) of acetic acid are added dropwise and the mixture is stirredfor 4 hours at room temperature. It is poured into ice-water andextracted with ethyl ether, and the organic phase is separated, washedwith water, dried over sodium sulphate and evaporated. The residueobtained is triturated in a hexane/ethyl ether mixture (50:50) filteredand dried. 1.7 g (89%) of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-teytrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethylamino]benzoicacid of melting point 165°-166° C. are collected.

EXAMPLE 312-Hydroxy-4-[[2-hydroxy-2-[3-(1-adamantyl)-4-methoxyphenyl]ethoxy]]benzoicacid

1.3 g (2.98 mmol) of 2-hydroxy-4-[[3-(1-adamantyl)-4-methoxybenzoyl]methoxy]benzoic acid, 200mg of 10% palladium on charcoal and 50 ml of dioxane are introduced intoa reactor. The mixture is hydrogenated at room temperature and under apressure of 7 bar for 4 hours, the catalyst is filtered and washed with50 of THF, and the filtrates are evaporated. The residue obtained ispurified by chromatography on a silica column, eluting with adichloromethane/methanol mixture (98:2). After evaporation of thesolvents, 1 g (77%) of the expected acid of melting point 178°-179° C.is collected.

EXAMPLE 322-Hydroxy-4-[[2-[3-(1-adamantyl)-4-methoxyphenyl]ethoxy]]benzoic acid

1.3 g (2.98 mmol) of 2-hydroxy-4-[[3-(1-adamantyl)-4-methoxybenzoyl]methoxy]benzoic acid, 800mg of 10% palladium on characoal and 100 ml of dioxane are introducedinto a reactor. The mixture is hydrogenated at room temperature under apressure of 7 bar for 4 hours, the catalyst is filtered and washed with50 ml of THF, and the filtrates are evaporated. The residue obtained ispurified by chromatography on a silica column, eluting with adichloromethane/methanol mixture (98:2). After evaporation of thesolvents, 790 mg (60%) of the expected acid of melting point 210°-211°C. are obtained.

B. EXAMPLES OF FORMULATION

1) ORAL ROUTE

a) 0.8 g tablet

Compound of Example 1 . . . 0.500 g

Pregelatinised starch . . . 0.100 g

Microcrystalline cellulose . . . 0.115 g

Lactose . . . 0.075 g

Magnesium stearate . . . 0.010 g

In this example, the compound of Example 1 can be replaced by the samequantity of the compound of Example 23.

b) Drinkable suspension in 5 ml ampoules

Compound of Example 2 . . . 0.500 g

Glycerol . . . 0.500 g

70% sorbitol . . . 0.500 g

Sodium saccharinate . . . 0.010 g

Methyl para-hydroxybenzoate . . . 0.040 g

Flavouring q.s.

Purified water q.s.p. . . . 5 ml

In this example, the compound of Example 2 can be replaced by the samequantity of the compound of Example 28.

(c) 0.2 g tablet

Compound of Example 3 . . . 0.001 g

Starch . . . 0.114 g

Bicalcium phosphate . . . 0.020 g

Silica . . . 0.020 g

Lactose . . . 0.030 g

Talc . . . 0.010 g

Magnesium stearate . . . 0.005 g

In this example, the compound of Example 3 can be replaced by the samequantity of the compound of Example 15.

(d) Drinkable suspension in 10 ml amploules

Compound of Example 4 . . . 0.200 g

Glycerol . . . 1.000 g

70% sorbitol . . . 1.000 g

Sodium saccharinate . . . 0.010 g

Methyl para-hydroxybenzoate . . . 0.080 g

Flavouring q.s.

Purified water . . . q.s.p. . . . 10 ml

(e) 0.5 q insoluble tablet

Compound of Example 5 . . . 0.050 g

Lactose . . . 0.082 g

Stearic acid . . . 0.003 g

Purified talc . . . 0.015 g

Sweetener . . . q.s.

Colorant . . . q.s.

Rice starch . . . q.s. . . . 0.500 g

(f) 0.8 g insoluble tablet

Compound of Example 6 . . . 0.010 g

Lactose . . . q.s.p. . . . 0.800 g

20% gum arabic in water . . . 0.080 g

Liquid paraffin . . . 0.004 g

Purified talc . . . 0.016 g

Starch . . . q.s.p. . . . 0.800 g

(g) 1 g capsules containing 0.5 g

Content of the capsule: Oily suspension

Content of Example 7 . . . 0.005 g

Paraffin oil . . . q.s.p. . . . 0.500 g

The casing of the capsule is made by moulding and then drying anappropriate mixture composed of: gelatine, glycerol, water andpreservative.

(h) Gelatine capsule containing 0.3 g of powder

Composition of the powder:

Compound of Example 14 . . . 0.100 g

Maize starch . . . 0.060 g

Lactose . . . q.s.p. . . . 0.300 g

The powder is packed into a gelatine capsule composed of gelatine, TiO₂and a preservative.

(i) 0.30 ml gelatine capsule

Opaque No. 3 standard calibre casing

Contents powder containing 0.1% by weight of active principle:

Compound of Example 17 . . . 0.3 mg

Magnesium stearate . . . 30 mg

Silica sold by the company DEGUSSA under the name Aerosil 200 . . . 30.0mg

Lactose . . . q.s.p. . . . 0.3 ml

2--TOPICAL ROUTE

(a) Non-ionic water-in-oil cream

Compound of Example 1 . . . 0.100 g

Mixture of emulsifying laolin alcohols, waxes and refined oils, sold bythe company BDF under the name "Anhydrous Eucerine" . . . 39.900 g

Methyl para-hydroxybenzoate . . . 0.075 g

Propyl para-hydroxybenzoate . . . 0.075 g

Sterile demineralised water q.s.p. . . . 100 g

In this example, the compound of Example 1 can be replaced by the samequantity of the compound of Example 8.

(b) Non-ionic oil-in-water cream

Compound of Example 2 . . . 1.000 g

Cetyl alcohol . . . 4.000 g

Glycerol monostearate . . . 2.500 g

PEG 50 stearate . . . 2.500 g

Karite butter . . . 9.200 g

Propylene glycol . . . 2.000 g

Methyl para-hydroxybenzoate . . . 0.075 g

Propyl para-hydroxybenzoate . . . 0.075 g

Sterile demineralised water q.s.p. . . . 100 g

In this example, the compound of Example 2 can be replaced by the samequantity of the compound of Example 10.

(c) Lotion

Compound of Example 19 . . . 0.100 g

Polyethylene glycol (PEG 400) . . . 69.900 g

95% ethanol . . . 30.000 g

In this example, the compound of Example 19 can be replaced by the samequantity of the compound of Example 21.

(d) Ointment

Compound of Example 20 . . . 0.020 g

Isopropyl myristate . . . 81.700 g

Liquid paraffin . . . 9.100 g

Silica sold by the company DEGUSSA under the name "Aerosil 200" . . .9.180 g

In this example, the compound of Example 20 can be replaced by the samequantity of the compound of Example 11.

(e) Ointment

Compound of Example 24 . . . 0.300 g

White petroleum jelly FP . . . q.s.p. . . . 100 g

In this example, the compound of Example 24 can be replaced by the samequantity of the compound of Example 31.

(f) Hydrophobic ointment

Compound of Example 25 . . . 0.300 g

Isopropyl myristate . . . 36.400 g

Silicone oil sold by the company RHONE POULENC under the name "Rhodorsil47 V 300" . . . 36.400 g

Beeswax . . . 13.600 g

Silicone oil sold by the company GOLDSCHMIDT under the name "Abil300.000 cst" . . . q.s.p. . . . 100 g

In this example, the compound of Example 25 can be replaced by the samequantity of the compound of Example 32.

(g) Hydrophilic ointment

Compound of Example 27 . . . 0.005 g

Anhydrous Eucerine . . . 60.000 g

Microcrystalline wax . . . 15.000 g

Liquid paraffin . . . q.s.p. . . . 100.000 g

(h) Ointment

Compound of Example 22 . . . 0.050 g

Stearyl alcohol . . . 3.000 g

Lanolin . . . 5.000 g

Petroleum jelly . . . 15.000 g

Distilled water . . . q.s.p. . . . 100.000 g

(i) Hydrophobic ointment

Compound of Example 26 . . . 1.000 g

Liquid paraffin . . . 9.100 g

Silica sold by the company DEGUSSA under the name Aerosil 200 . . .9.180 g

Isopropyl myristate . . . q.s.p. . . . 100.000 g

(j) Anionic O/W cream

Compound of Example 30 . . . 0.050 g

Sodium dodecyl sulphate . . . 0.800 g

Glycerol . . . 2.000 g

Stearyl alcohol . . . 20.000 g

Triglyerides of capric/caprylic acids sold by the company DYNAMIT NOBELunder the name Miglyol 812 . . . 20.000 g

Preservatives . . . q.s.

Demineralised water . . . q.s.p. . . . 100.000 g

(k) Water-eliminable ointment

Compound of Example 29 . . . 0.500 g

PEG 400 . . . 50.500 g

PEG 4000 . . . 25.000 g

Liquid paraffin . . . 15.000 g

What is claimed is:
 1. A diaromatic compound, having the followingformula: ##STR9## in which: R₁ represents --CH₃, --CH₂ OH, --COR₈ or--CH₂ OCOR₉,R₈ representing a hydrogen atom, OH, --OR₁₀, ##STR10## or alower alkyl radical, R₁₀ representing an alkyl radical having 1 to 20carbon atoms, an alkenyl radical having 2 to 20 carbon atoms, or an arylor aralkyl radical, r and r', identical or different, representing ahydrogen atom, a lower alkyl radical, an aryl radical, an aralkylradical, an α-aminoacid residue, a sugar residue or a heterocycle or rand r' taken together forming a heterocycle, R₉ representing an alkylradical having 1 to 20 carbon atoms, an alkenyl radical having 2 to 20carbon atoms or a sugar residue, R₂ represents --OR₁₁ or --OCOR₁₁ R₃represents a hydrogen atom, --OR₁₁ or --OCOR₁₁ R₁₁ representing ahydrogen atom, a lower alkyl radical, a fluoroalkyl radical having 1 to6 carbon atoms and 3 to 7 fluorine atoms, an aryl radical or an aralkylradical, R₄ represents a hydrogen atom, OH, a lower alkyl radical, analkoxy radical having 1 to 6 carbon atoms, a fluorine or chlorine atomor the --CF₃ group, R₅ and R₆ or R₆ and R₇ taken together form, with theadjacent aromatic ring, a ring with 5 or 6 members optionallysubstituted by methyl groups and optionally interrupted by an oxygen orsulphur atom, R₅ or R₇, whichever does not form the ring, is hydrogen, Xis a divalent radical which from left to right or conversely is selectedfrom the group consisting of:(i) --C(R₁₃ R₁₄)--C(R₁₆ R₁₈)--W--, and (ii)--C(R₁₃ R₁₄)--C(R₁₅ R₁₆)--C(R₁₈ R₂₀)-- in which: W represents an oxygenatom, --NR₁₂ or S(S)_(n), n being 0, 1 or 2, R₁₃, R₁₅ and R₂₀ representa hydrogen atom, --OR₁₁, ##STR11## an aralkyl radical, a lower alkylradical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical, r"and r"', identical or different, representing a hydrogen atom, a loweralkyl radical, an alkenyl radical having 2 to 6 carbon atoms or analkynyl radical having 2 to 6 carbon atoms, R₁₄, R₁₆ and R₁₈ represent ahydrogen atom, an aralkyl radical, a lower alkyl radical, or amonohydroxyalkyl or polyhydroxyalkyl radical, when X represents (i), R₁₃and R₁₄ together can form a ═N--OR₁₁ group or a ═N--OCOR₁₁ group, andwhen X represents (ii) R₁₄, R₁₆ and R₁₈ can also represent --0R₁₁ or--OCOR₁₁ or R₁₃ and R₁₄ or R₁₅ and R₁₆ taken together can form a ═NOR₁₁group or a ═N--OCOR₁₁ group, R₁₂ representing a hydrogen atom, a loweralkyl radical, an aralkyl radical, an alkenyl radical having 2 to 6carbon atoms, an alkynyl radical having 2 to 6 carbon atoms or afluoroalkyl radical having 1 to 6 carbon atoms and 3 to 7 fluorineatoms, or a salt of the compound of formula (I) when R₁ represents acarboxylic acid function or when R₁₃, R₁₆ or R₂₀ represents an aminefunction, or an optical isomer of the compound of formula (I).
 2. Thecompound according to claim 1, wherein said compound is present in theform of a salt of an alkali metal or alkaline earth metal or of zinc orof an organic amine.
 3. The compound according to claim 1, wherein saidcompound is present in the form of a salt of an inorganic or organicacid selected from the group consisting of hydrochloric, sulfuric,acetic, citric, fumaric hemisuccinic, maleic and mandelic acid.
 4. Thecompound according to claim 1, wherein said lower alkyl radical isselected from the group consisting of methyl, ethyl, isopropyl, butyland tertiary butyl.
 5. The compound according to claim 1, wherein saidalkoxy radical is selected from the group consisting of methoxy, ethoxy,isopropoxy and butoxy.
 6. The compound according to claim 1, whereinsaid monohydroxyalkyl radical is selected from the group consisting of2-hydroxy-ethyl, 2-hydroxypropyl and 3-hydroxypropyl.
 7. The compoundaccording to claim 1, wherein said polyhydroxyalkyl radical is selectedfrom the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl radical and pentaerythritol residue.
 8. Thecompound according to claim 1, wherein said aryl radical is a phenylradical optionally substituted by at least one halogen atom, hydroxyl ornitro function.
 9. The compound according to claim 1, wherein saidaralkyl radical is a benzyl or phenethyl radical optionally substitutedby at least one halogen atom, hydroxyl, or nitro function.
 10. Thecompound according to claim 1, wherein said alkynyl radical ispropargyl.
 11. The compound according to claim 1, wherein said alkenylradical having 2 to 6 carbon atoms is selected from the group consistingof vinyl, allyl and 2-butenyl.
 12. The compound according to claim 1,wherein said heterocycle is selected from the group consisting ofpiperidino, morpholino, pyrrolidino and piperazino, optionallysubstituted in 4 position by a C₁ -C₆ alkyl or mono- or polyhydroxyalkylradical.
 13. The compound according to claim 1, wherein said compound isselected from the group consistingof:2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid; methyl2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate;2-hydroxy-4-[2-hydroxyimino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-acetoxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)ethoxy]benzoicacid;2-hydroxy-4-]2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol; acetate of2-acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol;N-piperidinyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]-benzamide;N-morpholinyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]-benzamide;2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide;N-ethyl-2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzamide:methyl2-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoate;2-hydroxy-4-[2-hydroxy-2-(4,4-dimethylthiochroman-6-yl)ethoxy]benzoicacid;2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyl]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]toluene;methyl2,6-dihydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate;(-) isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid; (+) isomer of2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy[benzoicacid;2-methoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-amino-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyloxy]benzoicacid;2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hexyloxy[benzoicacid; and2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethylamino]benzoicacid.
 14. A pharmaceutical composition, wherein said compositioncontains at least one compound of formula (I) according to claim 1 in anappropriate vehicle, for administration by the enteral, parenteral,topical or ocular route.
 15. A composition according to claim 14,wherein said composition contains 0.001 to approximately 5% by weight ofa compound of formula (I).
 16. A cosmetic composition for body and hairhygiene, wherein said composition contains at least one compound offormula (I) according to claim 1 in an appropriate cosmetic vehicle. 17.A cosmetic composition according to claim 16, wherein said compositioncontains the compound of formula (I) at a concentration of between 0.001and 3% by weight.
 18. Method of treatment of dermatological, rheumatic,respiratory or ophthalmological conditions comprising administering to apatient suffering from at least one of said conditions a therapeuticallyeffective amount of a compound of claim 1.